This grant will support research in two areas: lipoprotein structure and molecular immunology. The common thread is our interest in the structure of functional macromolecular complexes formed between proteins and lipids and receptors, and between antibodies, antigen, and complement. The goals of the lipoprotein projects are to (1) determine the conformation of apolipoprotein B on the surface of the low density lipoprotein, and the location of the site on apo B recognized by the receptor; (2) to determine the number of apo B48 molecules on the chylomicrons, and to examine the confomation of apo B100 on the VLDL; (3) to characterize the structure of recombinant apolipoprotein(a) and its complex with LDL which forms the highly atherogenic Lp(a). The goals of the molecular immunology projects are (1) to determine the nature of the conformational changes through which IgM acquires the ability to bind and activate complement; (2) to develop a new technique we call 'targeted immunogenesis' to form monoclonal antibodies to selected regions on a protein. These monoclonals will be used as probes of IgM structure and function. (3) to study protein protein interactions by equilibrium dialysis, employing a special membrane not previously used for such studies. This technique will then be employed in both the lipoprotein and immunoglobulin projects. The methodology includes analytical ultracentrifugation, circular dichroism, fluorescence, and electron microscopy, as well as the production of monoclonal antibodies and recombinant DNA techniques. These projects are related to problems of health; thus (1) high concentrations of chylomicron and VLDL remnants remaining after lipolysis, and especially high concentrations of LDL, are closely associated with the development of the atherosclerotic lesion, and associated heart attack, senility and stroke; (2) the triggering of complement and cells by immune complexes and antigens is a critical feature of the immune defense against bacterial and viral challenge.